PROJECT SUMMARY Hypertension is the most common primary diagnosis in the United States, and even treated individuals remain at elevated cardiovascular risk, suggesting that current therapeutic options are suboptimal. Emerging evidence implicates activation of the immune system as a central feature of hypertension, particularly CD4+ T helper lymphocytes and T cell-derived cytokines. Hypertension is characterized by infiltration of T lymphocytes into end-organs such as the vasculature, kidney, and heart. Interleukin-21 (IL-21) is a pro-inflammatory cytokine produced by multiple T helper subsets that potentiates IL-17A production by T helper cells. A recently described CD4+ subset of T peripheral helper cells (TPH) cells were shown to produce IL-21 in the context of autoimmune disease. IL-17A is a cytokine known to contribute to immune activation in hypertension and act directly on the endothelium. Preliminary studies have shown that IL-21 deficient mice have a blunted hypertensive response, and neutralization of IL-21 both reverses endothelial dysfunction and lowers blood pressure in mice. This compelling evidence suggest that IL-21 is a key cytokine driving activation of the adaptive immune system and end-organ damage in hypertension; however, which T cell subsets produce IL-21 in hypertension and whether IL-21 acts directly on the endothelium is unknown. This project will (a) test the hypothesis that TPH cells are the primary source of IL-21 in hypertension and that IL-21 producing T cells are sufficient to promote hypertension in vivo, (b) mechanistically determine the role of IL-21 in endothelial dysfunction and (c) evaluate the long-term impact of cytokine-neutralizing therapy on clinical cardiovascular outcomes. The completion of these studies will yield critical insights into the mechanism underlying immune activation in hypertension and identify potential novel cellular targets.